A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis
- Conditions
- Cystic Fibrosis
- Interventions
- Registration Number
- NCT02951182
- Lead Sponsor
- Vertex Pharmaceuticals Incorporated
- Brief Summary
This is a Phase 2, randomized, double-blind, placebo- and active-controlled, parallel group, multicenter study to evaluate the safety, tolerability, and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ and/or IVA therapy (F508del/MF).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 74
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Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
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To prevent pregnancy, female participants of childbearing potential and their male partners will be required to use pre-specified, highly effective methods of non-hormonal contraception. Male participants with female partners of childbearing potential will be required to use a condom.
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Body weight ≥35 kg.
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Sweat chloride value ≥60 mmol/L from test results obtained during screening.
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Subjects must have an eligible CFTR genotype:
- Heterozygous for F508del and a minimal function (MF) mutation known or predicted not to be responsive to TEZ and/or IVA.
- Homozygous for F508del
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Subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height at the Screening Visit
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Stable CF disease as judged by the investigator.
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Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow up Visit.
- History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
- History of cirrhosis with portal hypertension.
- Risk factors for Torsade de Pointes
- History of hemolysis.
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency assessed at Screening.
- Clinically significant abnormal laboratory values at screening
- An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before the first dose of study drug.
- Lung infection with organisms associated with a more rapid decline in pulmonary status
- An acute illness not related to CF within 14 days before the first dose of study drug
- A standard digital ECG demonstrating QTc >450 msec at screening.
- History of solid organ or hematological transplantation.
- History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period.
- History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
- Ongoing or prior participation in an investigational drug study, with certain exceptions. (e.g., ongoing participation in NCT02565914)
- Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days before screening (applies only to the Heterozygous F508del/MF cohorts; does not apply to the Homozygous F508del/F508del Cohort).
- Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1 Cohort 1B: TC High Dose VX-440 Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks. Part 1 Cohort 1B: TC Low Dose VX-440 Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks. Part 1 Cohort 1A: Triple Combination (TC) TEZ Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks. Part 2: TC-2 VX-440 Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. Part 1 Cohort 1B: TC High Dose IVA Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks. Part 2: TEZ/IVA TEZ Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. Part 1 Cohort 1A: Triple Combination (TC) VX-440 Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks. Part 1 Cohort 1B: TC High Dose TEZ Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks. Part 2: TEZ/IVA Matched Placebo Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. Part 2: TEZ/IVA IVA Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. Part 1: Placebo - Cohort 1A and 1B Combined Matched Placebo Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks. Part 1 Cohort 1A: Triple Combination (TC) IVA Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks. Part 1 Cohort 1B: TC Low Dose IVA Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks. Part 1 Cohort 1B: TC Low Dose TEZ Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks. Part 2: TC-2 TEZ Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. Part 2: TC-2 IVA Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
- Primary Outcome Measures
Name Time Method Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) From first dose of Study Drug in the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2) Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
- Secondary Outcome Measures
Name Time Method Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline at Day 29 The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA Predose at Day 8, Day 15 and Day 29 Relative Change in ppFEV1 From Baseline through Day 29 FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Absolute Change in Sweat Chloride Concentrations From Baseline through Day 29 Sweat samples were collected using an approved collection device.
Trial Locations
- Locations (40)
St. Luke's CF Center of Idaho
🇺🇸Boise, Idaho, United States
The University of Texas Southwestern Center
🇺🇸Dallas, Texas, United States
St. Michael's Hospital
🇨🇦Toronto, Ontario, Canada
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital Cystic Fibrosis Center
🇺🇸Boston, Massachusetts, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Stanford University
🇺🇸Palo Alto, California, United States
Joe Di Maggio Cystic Fibrosis & Pulmonary Center
🇺🇸Hollywood, Florida, United States
Cystic Fibrosis Center of Chicago
🇺🇸Glenview, Illinois, United States
The Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
New York Medical College
🇺🇸Hawthorne, New York, United States
Long Island Jewish Medical Center
🇺🇸New Hyde Park, New York, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Sanford Children's Specialty Clinic Sanford Research USD
🇺🇸Sioux Falls, South Dakota, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
UPMC OSPARS Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Children's Hospital of the Kings Daughters
🇺🇸Norfolk, Virginia, United States
Royal Adelaide Hospital
🇦🇺Adelaide, Australia
Prince Charles Hospital
🇦🇺Chermside, Australia
Medizinische Universitat Innsbruck
🇦🇹Innsbruck, Austria
Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
🇧🇪Leuven, Belgium
Mukeviszidose-Zentrum am Universtitatsklinikum Jena
🇩🇪Jena, Germany
University Hospital Cologne
🇩🇪Koeln, Germany
Pneumologische Praxis Pasing
🇩🇪Muenchen, Germany
Hospital Universitari Vall d´Hebron Servicio de Broncoscopia
🇪🇸Barcelona, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Seville, Spain
Heart of England NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Southampton University Hospitals NHS Foundation Trust
🇬🇧Southampton, United Kingdom
Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital
🇬🇧London, United Kingdom
The Arizona Board of Regents on behalf of the University of Arizona
🇺🇸Tucson, Arizona, United States
Universitair Ziekenhuis Brussel
🇧🇪Brussels, Belgium
St. Paul's Hopsital
🇨🇦Vancouver, British Columbia, Canada
Juliane Marie Center, Righospitalet
🇩🇰Copenhagen, Denmark
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
John Hunter Hospital & Hunter Medical Research Institute
🇦🇺New Lambton Heights, Australia
University of California
🇺🇸San Francisco, California, United States
National Jewish Health
🇺🇸Denver, Colorado, United States
Central Florida Pulmonary Group
🇺🇸Orlando, Florida, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Respiratory Diseases of Children and Adolescents
🇺🇸Oklahoma City, Oklahoma, United States